A number of pathophysiologic diseases have been classified as involving “amyloidosis,” which are characterized by the deposition of abnormal fibrils (“amyloid fibrils”) in extracellular spaces. The amyloid fibril formation is thought to represent a final common result from the misfolding of a diverse array of proteins. Regardless of their biochemical composition, all types of amyloid fibrils share certain characteristics, including: a β-pleated sheet structure; green birefringence under polarized light after staining with Congo Red dye; and a fibrillar morphology in electron micrographs.
The deposition of amyloid fibrils affects several organs. One type of amyloid fibril causes “cerebral amyloidosis,” which covers the Alzheimer group of diseases, namely, Alzheimer's disease (e.g., pre-senile dementia, senile dementia); Alzheimer's disease associated with Down's syndrome; Alzheimer's disease associated with other central-nervous-system diseases, such as Parkinson's disorder; and congophilic angiopathy (whether or not associated with Alzheimer's disease).
Presently, there is no effective therapy for cerebral amyloidosis, which was a fatal outcome following the onset of amyloid deposits. Alzheimer's disease (AD) is estimated to be the fourth or fifth leading cause of death among North Americans. Accumulating biochemical, histological, and genetic evidence supports the hypothesis that the 4 kDa β-amyloid protein (Aβ) is an essential component in the pathogenesis of Alzheimer's disease. Selkoe D J, Science 275:630-631 (1997); Hardy J, Proc Natl Acad Sci USA 94:2095-2097 (1997). Despite the intense interest in the role of Aβ in the etiology of AD, the role of Aβ in fibril formation is poorly understood.